Process for preparing alpha-acylamido acetoacetic ester



Patented Sept. 12, 1950 PRooEss FOR PREPAIHfiGo-ACYTQAMIDU ACETOACETICTESTER Boil'n'dbrtti'oli,'NTJJ assignors to Merck & (30.,

Inc.,"RahWay',N. 'J.',' a corporation of New Jersey No' Drawingr Original application February 9,

1940, Serial ;No.,646,701. Divided and this ap plication October 29, 1949,"Serial No. 124,488

This'ls a -ilivisiol'fof 0111" pending application; Serial No. 646,701, filed February "9, 19461 This 'inventionrelates to processes for preparimgwacmamiuo acetic'ester' compounds and 'particularly to the" preparation or such" compounds from corresponding a-isonitroso acetic" I esters. a-Acylamido acetic esters: and particularly those having an asubstituent of the class 'con'si'stingoi': acyl," ester; and cyandradi'cal's are useful as interi'nediatesin chemical: processes "such as the synthesis of "amino acids."

Acylanfidom'al'onic esters represent a compara tivelynew'typeof compound, and were first pre pared by reacting aminom'alonic esters "with acylating agents such as acetylchloride(Cerchez; nuli s'o'c'r chemi'aeyis m (19310 I acylat ionprocedure of this publication gives high per "cent conversion of aminbmalonic' esterto acetamido "malonic "ester," aminoinalonic ester' is itself unstable and can be made onlyin relatively poor"yields"withthe result that overall yield of acetamido malonic ester 'fro'm" malonic ester'b-y It has also been disclosed by Snyder andSmith, J. A. C. S. 66, 350 (1944) ,thatacetamido malonic ester can be prepared by subjecting isonitroso malonic ester-(obtainedby-the procedure *of' Ce-rchezfBul; Chem-1 $00547, 1279 "(1930)? to catalytic reduction in ethanol with "a palladium charcoal ascatalyst and, after--removalof the catalyst,'acetylating with acetic-"anhydride. This preparation of" acetamido maloiiic ester; howeven-results-in only'a 40% yield based upon-the malon-ic ester used,- andis subjec't tothe further disadvantage that-the catalystis easily poisoned.

It is -now discovered, in accordance with the present -invention,-'- that it is possible to obtain a-acylamido acetic ester compounds in very good yields'by first preparing-the-a-isonitroso (or as alternatively termed the a-oximino) derivative of the ester and subjecting the same to reductive acylation with powdered-zinc or powdered iron as a reducing agent.

Regarded in I certain of its broader aspects, the novel process according to the present invention comprises reacting a-isonitro'so a-(XT' acetic ester, wherein X is of the class consisting of acyl, ester, and cyano radicals,'with a lower aliphatic carboxylic" acid, its anhydride; and'a reducing agent of the class consisting of powdered zinc and powdered iron; "and-recovering from the reaction mixture the 'corresponding a-acylamido a- (X) acetic ester.

In preparing the reaction medium, the r'educ-' ing agent ca'nbead'ded' tethecodled (-'-20 (3;)

While the" mixture of acid'and anhydride slowly and with vigorous 'stirring',"or alternatively, the a-isonitroso acetic ester compound can be first mixed withthe acid and anhydride."

Reduction-and simultaneous acylation usingthe'tvpe reaction medium first mentioned above is'effected' by adding the a-isonitroso acetic ester" compound slowly, with stirring; to the mixture of reactants while cooling to maintain proper tem'- perature, the reaction being exothermic. If the a-iSOIliTJL'OSO' acetic ester compound is not a liquid,

it can-be mixed with some of the acid orlsolvent employed in the mixture above referred to.

When zinc dustis used as the reducing agent, the temperature is preferably held between 10" and*-2(l" C. during this addition. When iron dustor iron powder is used as thereducing agent, the temperature must be held at a slightly higher level, 25 to 35 0., during theaddition, as lower temperatures retard the reaction, allowing for accui'nulation of unreacted material which may react violentlyonc'ethe reaction is underway.

' Afterthe additionis completed, thereaction mixt'ureis stirred =i0r a more or less extended" period (2 to '18 hours depending on the partic'ular" compound being prepared) to permit the reaction to'go to completion; The reaction is exothermic and the" heat of reaction will raise the' 'temper'a-" ture somewhat above room temperature. A slight rise'intemperature during this period'i's not objectionable and external cooling is'not generally necessary. When the'reaction is complete,"th' drop in temperature of the reaction mixture indica-tes -thatstirring can be discontinued." The reaction mixture is then filtered and worked up by'conventional isolation and purification steps to yield the crystalline *ai-acvlamido acetic estercompound:

The second a substituent, i.'e.,'the'acyl, ester, or' -cyano radical, in the a-lSOIlitlOSO acetic ester" compounds does not affect" the reaction, and com"-' poundsha'ving any acylor ester group orthe cyano radical' 'as the secondd substituent' can be" reacted in'the manner described to yieldthe"cor-' responding; substituted z'z-acylamido acetic ester;'

In the reductive acylation' reaction, the various' reactants are employed in the 'following approx-" imate-"proportions'f- 1 moleof the a-isonitroso acetic estercompound; 2.9 moles orthe organic acid'anhydride; 14.2 moles of the organic 'carboxy1ic'acid,"and"5.5"to 6.5 moles of thereducing" agent (zinc or iron). Increasing the molarpr'oportion of the anhydride serves no useful purpose as it does not increase the yield. The molar pro-5f portion of the reducing agent should hot be low 3 ered appreciably below the range given above as this results in a low yield and low melting or impure product.

When the second type reaction medium is employed (i. e., the a-isonitroso acetic ester compound is first mixed with the acid and anhydride) the reactants are used in the same molar ration as that given above except that the amount of zinc dust used may be reduced to 3.85 moles. The reducing agent is added slowly with stirring'to the reaction medium; however, with this procedure, it is not necessary to cool the reaction medium during the addition. The heat of reaction, when the reducing agent is added over a period of about 1% hours, will maintain a temperature of about 40 to 50 C. The markedly exothermic reaction is completed by the end of the addition of reducing agent or slightly prior thereto, and it is not essential to continue agitation of the reaction mixture for more than about one-half hour after all of the reducing agent has been added.

Comparable yields are obtained by the two procedures. For example, the yield of acetamido malonic ester, based upon the amount of malonic ester originally used, is about 84% when the reaction is carried out by adding the a-iSolflitlOSO compound to the other reactants, and about 81.5% when the Zinc dust is added to the other reactants. The slightly lower yield by the latter procedure is more than offset by the fact that this procedure is more economical, particularly in that cooling is completely eliminated, time of reaction is reduced, and less zinc dust is required.

. The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

Example I Equip a dry 500 ml. three-necked, round-bottomed flask with a stirrer and immersion thermometer, and mount in an ice bath. After placing60 g. of acetic anhydride (.586 mole) and 170 m1. of glacial acetic acid (2.84 moles) in the flask, cool the solution to 10 C. and add, with vigorous stirring, 83.5 g. of zinc dust (1.28 moles) over a period of 15 minutes. The mixture is cooled again to about 10 C. before the addition of the isonitroso malonic ester is started.

- With stirring, add 37.8 g, of the diethyl ester of isonitroso malonic acid (.2 mole) from a 100 ml. dropping funnel, keeping the temperature below C. The addition requires about 2 hours and must be carried out slowly since the reaction is quite exothermic. When all the oil has been added, remove the flask from the ice bath and stir at room temperature for four hours. During this period, the temperature reaches a maximum of 3.8-40 C. Prolonging the stirring to eight hours after the addition of the isonitroso does not improve the yield of acetamino malonic ester.

Filter the reaction mixture and wash the residue thoroughly with three-100 ml. portions of glacialacetic acid. After combining the washings and filtrate, concentrate the whole in vacuo to a thick oil which sometimes partially crystallizes, and remove last traces of solvent by adding 100 ml. of water and concentrating again. tain a nicely crystalline product, add 100 ml. of water, and heat the flask on a steam bath until the solid melts. Next stir the mixture of oil and water vigorously while cooling in .an ice bath. The diethyl ester of acetamino malonic acid precipitates out immediately as fine white crystals. Chill in the ice box for three hours or longer,

To ob-- 4 filter and wash with three ml. portions of ice cold water. After drying in a hot air oven at 50 C. overnight, the yield of acetamino malonic ester is 84% (36.4 g.) The product melts at 9497 0., and can be condensed with gramine without further purification to prepare skatylacetamido malonic ester in the gramine synthesis of trypto phane.

Example II Into a 500 cc. three-necked flask equipped with a mechanical stirrer, a dropping funnel and a condenser through which is suspended an immersion thermometer are introduced 60 grams of acetic anhydride and 170 cc. of glacial acetic acid. The solution is cooled to 20 C. whereupon 71.5 g. (1.28 moles) of iron dust are added with vigorous stirring. The mixture is then brought to room temperature and 37.8 g. of ethyl isonitrosomalonate are added over a period of two hours during Which time the temperature is maintained between 25-35 C.

The isonitroso malonic ester addition must not be started below 25 C, since at lower temperatures the reaction proceeds very slowly, thus allowing the accumulation of considerable unreacted material which may react violently once the reaction is underway.

After all of the ester has been added, the ice bath is removed and the mixture is stirred at room temperature for four hours. The mixture is filtered and the solid is Washed with 5x100 cc. of glacial acetic acid. The dark red filtrate and washings are combined and concentrated under reduced pressure to a heavy oil. 100 cc. of water are added and the solution i again concentrated. The residue is dissolved in 100 cc. of boiling water, after which the solution is chilled in an ice bath with rapid stirring. Fine white crystals of ethyl acetamidomalonate separate. After three hours in the ice bath, the crystals are collected on a Buchner funnel and washed with 3x100 and 2x50 cc. of ice Water. Yield: 23.9 g.-55%; M. P. 95-97 C.

Example 11.!

I The procedure described in Example I is repeated using in place of the acetic acid and acetic anhydride about 210 cc. (2.84 moles) of propionic acid and about 76 g. (.585 mole) of propionic anhydride. During the addition of ethyl isonitroso malonate, the temperature is kept below 20 C., and after the completion of this addition, the mixture is stirred for an extended period, about 18 hours, during which time the temperature is maintained at about 30-3l C. by the heat reaction. The reaction mixture is worked up as described in Example I and, after recrystallization from 95% ethanol, a yield of about 40% of the diethyl ester of propionamido maloni-c acid, melting at 92-94 C. is obtained. The elementary analysis is as follows: Theory: 52% C', 7.37% H, 6.07%, N. Found: 52.19% C, 7.36% H, 6.33% N. Additional amounts of th product can be recovered by working up the mother liquors.

Example I V A solution of about 31.8 g. (0.2 mole) of the ethyl ester of a-isonitroso acetoacetic acid, M. P. 5659 C. (prepared according to the procedure disclosed by Adkins and Reeve, J. A. C. S. 60, 1328 (1938)) in about 30 cc. of glacial acetic acid is added dropwise over a period of about two hours to a well-stirred mixture of cc. of

glacial acetic acid, 55 cc. (.585 mole) of acetic anhydride and about 83.5 g. (1.28 moles) of zinc dust. During the addition, the temperature is held at about -15 C. by ice cooling. The ice is then removed and the mixture is stirred for about four hours during which time the temperature rises to a maximum of 30 C. due to heat of reaction. The reaction mixture is filtered and washed with about four cc. portions of glacial acetic acid. The water-white filtrate is concentrated by heating to about 60 C. under reduced pressure (first slightly reduced and then lowered to about '7 mm. until nothing further distills off. The remaining pinkish oil (about 41.8 g.) is treated with 25 cc. of water and then extracted with two 50 cc. portions and then with two 25 cc. portions of chloroform. The extract is washed with water, sodium bicarbonate solution and some water, and is then dried over sodium sulfate and concentrated to constant weight under vacuum. About 35.1 g. (93.8% of theory) of ethyl acetamidoacetoacetate is recovered as a viscous oil which crystallizes upon cooling. The nearly white crystalline product melts at about 45-48 C. Purification by recrystallization from toluene yields a product melting at about 47.548.5 C. and having the following partial analysis: Calculated: 51.34% C, 6.95% H. Found: 51.56% C, 7.08% H.

Example V A solution of about 14.2 g. (0.1 mole) of the ethyl ester of a-iSOIlitIOSO cyanoacetic acid (prepared according to the procedure of Conrad and Schulze, Ber. 42, 736 (1909) and melting at about 127-129 C.) in about 40 cc. of glacial acetic acid is added dropwise over a period of about one hour to a well-stirred mixture of about 55 cc. of glacial acetic acid, 27.6 cc. (1.292 moles) of acetic anhydride and 41.8 g. (.64 mole) of zinc dust while maintaining the temperature at about 10-15 C. with ice cooling. Considerable heat is evolved in the reaction. After completion of the addition, the reaction mixture is stirred for about two hours with cooling, if necessary, to keep the temperature below about 30 C. The reaction mixture is then filtered and the residue washed with glacial acetic acid. The water-white filtrate and washings are concentrated to dryness under vacuum, yielding white needle crystals. After recrystallization from about 80 cc. of hot water, about 10.7 g. (63% of theory) of the ethyl ester of a-acetamidocyanoacetic acid melting at about 129-130 C. is obtained as a first crop having the following partial analysis: Calculated: 49.40% C, 5.92% H. Found: 49.43% C, 5.99% H. Additional product can be obtained by working up the mother liquors.

Example VI About g. (1.23 moles) of zinc dust is added slowly to an agitated solution of about 58.5 g. (0.31 mole) of the diethyl ester of a-isonitroso malonic acid in 225 cc. of glacial acetic acid and 80 cc. (0.84 mole) of acetic anhydride. The addition is made over a period of about 1 /2 hours without external cooling of the reaction mixture. The reaction is markedly exothermic during the first seven-eighths of the addition, maintaining a temperature of about 40-50 C. in the reaction mixture, and thereafter evolution of heat drops off. The mixture is agitated, without cooling, for about one-half hour after all the Zinc dust is added. The mixture is then filtered, the solid is washed with glacial acetic acid, and the combined filtrate and washings are worked up as in Example I, yielding about 55.3 g. (81.5% based upon malonic ester) of the diethyl ester of acetamido malonic acid, M. P. -9? C.

Example VII The procedure of Example VI is repeated with the exception that the temperature is held at about 18-20 C. during the addition of zinc dust, and after completion of the addition, the mixture is agitated for about four hours without cooling. The yield of the diethyl ester of acetamido malonic acid, M. P. 95-97 C., is about 81.5%.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof, and the invention is to be limited only by the appended claims.

What is claimed is:

1. The process that comprises reacting an a-iSOIlitI'OSO acetoacetic ester with an anhydrous mixture of a lower alkyl carboxylic acid and its anhydride in the presence of a reducing agent of the class consisting of powdered zinc and powdered iron, and recovering from the reaction mixture the corresponding a-acylamido acetoacetic ester.

2. The process that comprises reacting c-isonitroso acetoacetic ester with an anhydrous mixtur of glacial acetic acid and acetic anhydride in the presence of zinc dust, and recovering from the reaction mixture a-acetamido acetoacetic ester.

3. The process for preparing ethyl acetamidoacetoacetate which comprises treating a mixture of ethyl oximinoacetoacetate, acetic anhydride, and acetic acid with zinc dust.

MAX 'IISHLER. EUGENE E. HOWE.

No references cited. 

1. THE PROCESS THAT COMPRISES REACTING AN A-ISONITROSO ACETOACETIC ESTER WITH AN ANHYDROUS MIXTURE OF A LOWER ALKYL CARBOXYLIC ACID AND ITS ANHYDRIDE IN THE PRESENCE OF A REDUCING AGENT OF THE CLASS CONSISTING OF POWDERED ZINC AND POWDERED IRON, AND RECOVERING FROM THE REACTION MIXTURE THE CORRESPONDING A-ACYLAMIDO ACETOACETIC ESTER. 